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Efficacy and safety of an intraoral electrostimulation device for xerostomia reliefA multicenter randomized trial.

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ARTHRITIS & RHEUMATISM
Vol. 63, No. 1, January 2011, pp 180–190
DOI 10.1002/art.27766
© 2011, American College of Rheumatology
Efficacy and Safety of an Intraoral Electrostimulation Device
for Xerostomia Relief
A Multicenter, Randomized Trial
Frank P. Strietzel,1 Gloria I. Lafaurie,2 Gloria R. Bautista Mendoza,2 Ivan Alajbeg,3
Slavica Pejda,3 Lea Vuletić,3 Rubén Mantilla,4 Denise P. Falcão,5 Soraya C. Leal,5
Ana C. Barreto Bezerra,5 Simon D. Tran,6 Henri A. Ménard,7 Suguru Kimoto,8 Shaoxia Pan,9
Rafael A. Martı́n-Granizo,10 M. Lourdes Maniegas Lozano,10 Susan L. Zunt,11
Cheryl A. Krushinski,11 Dario Melilli,12 Giuseppina Campisi,12 Carlo Paderni,12 Sonia Dolce,12
Juan F. Yepes,13 Liselott Lindh,14 Meltem Koray,15 Gonca Mumcu,16 Sharon Elad,17
Itai Zeevi,17 Beatriz C. Aldape Barrios,18 Rodrigo M. López Sánchez,18 Ben Z. Beiski,19
Andy Wolff,19 and Yrjö T. Konttinen20
Objective. To evaluate the efficacy and safety of an
intraoral electrostimulation device, consisting of stimu-
lating electrodes, an electronic circuit, and a power
source, in treating xerostomia. The device delivers electrostimulation through the oral mucosa to the lingual
nerve in order to enhance the salivary reflex.
Methods. The device was tested on a sample of
patients with xerostomia due to Sjögren’s syndrome and
other sicca conditions in a 2-stage prospective, randomized, multicenter trial. Stage I was a double-blind,
crossover stage designed to compare the effects of the
electrically active device with the sham device, each used
for 1 month, and stage II was a 3-month open-label
stage designed to assess the long-term effects of the
active device. Improvement in xerostomia severity from
baseline was the primary outcome measure.
Results. A total of 114 patients were randomized.
In stage I, the active device performed better than the
ClinicalTrials.gov identifier: NCT00509808.
Drs. Tran and Ménard’s work was supported by funding from
the Canadian Institutes of Health Research to McGill University
(CIHR Program to Stimulate International Research Initiatives). Dr.
Lindh’s work was supported by funding from the Swedish Laryng
Foundation to Malmö University. Dr. Konttinen’s work was supported
by funding from the Academy of Finland, Finska Läkaresällskapet,
Helsinki University Central Hospital, and the ORTON Foundation to
the University of Helsinki. Saliwell Ltd. (Harutzim, Israel) provided
the intraoral electrostimulation devices for the study at no charge.
1
Frank P. Strietzel, MD, DDS: Charité Universitätsmedizin
Berlin, Berlin, Germany; 2Gloria I. Lafaurie, DDS, Gloria R. Bautista
Mendoza, MS Statistics: Universidad El Bosque, Bogotá, Colombia;
3
Ivan Alajbeg, DMD, PhD, Slavica Pejda, DDM, Lea Vuletić, DMD:
University of Zagreb, Zagreb, Croatia; 4Rubén Mantilla, MD: Clı́nica
de Artritis y Rehabilitación, Bogotá, Colombia; 5Denise P. Falcão,
MHS, Soraya C. Leal, PhD, Ana C. Barreto Bezerra, DMD, PhD:
Universidade de Brasilia, Brasilia, Brazil; 6Simon D. Tran, DMD,
PhD: McGill University, Montreal, Quebec, Canada; 7Henri A. Ménard, MD: McGill University and McGill University Health Center,
Montreal, Quebec, Canada; 8Suguru Kimoto, DDS, PhD: Nihon
University School of Dentistry at Mastudo, Mastudo, Japan; 9Shaoxia
Pan, DMD: Hospital of Stomatology and Peking University, Beijing,
China; 10Rafael A. Martı́n-Granizo, MD, M. Lourdes Maniegas
Lozano, MD, DMD: Hospital Clı́nico San Carlos, Madrid, Spain;
11
Susan L. Zunt, DDS, MS, Cheryl A. Krushinski, DDS: Indiana
University, Indianapolis; 12Dario Melilli, DMD, Giuseppina Campisi,
DMD, PhD, Carlo Paderni, DMD, Sonia Dolce, DMD: Università di
Palermo, Palermo, Italy; 13Juan F. Yepes, DDS, MD, MPH: University
of Kentucky, Lexington; 14Liselott Lindh, DDS, PhD: Malmö University, Malmö, Sweden; 15Meltem Koray, DDS, PhD: Istanbul University, Istanbul, Turkey; 16Gonca Mumcu, DDS, PhD: University of
Marmara, Istanbul, Turkey; 17Sharon Elad, DMD, MSc, Itai Zeevi,
DMD: Hebrew University Hadassah School of Dental Medicine,
Jerusalem, Israel; 18Beatriz C. Aldape Barrios, DDS, Rodrigo M.
López Sánchez, DDS: Universidad Nacional Autónoma de Mexico,
Mexico City, Mexico; 19Ben Z. Beiski, MS, Andy Wolff, DMD: Saliwell
Ltd., Harutzim, Israel; 20Yrjö T. Konttinen, MD, PhD: Helsinki
University Central Hospital, University of Helsinki, and ORTON
Orthopaedic Hospital, Helsinki, and COXA Hospital for Joint Replacement, Tampere, Finland.
Dr. Zunt served as principal investigator in a study funded by
Parion Sciences. Mr. Beiski and Dr. Wolff own stock in Saliwell Ltd.
and hold patents as coinventors of intraoral electronic medical devices.
Address correspondence to Andy Wolff, DMD, Saliwell Ltd.,
65 Hatamar Street, Harutzim 60917, Israel. E-mail: awolff@zahav.
net.il.
Submitted for publication April 14, 2010; accepted in revised
form September 21, 2010.
180
ELECTROSTIMULATION DEVICE FOR XEROSTOMIA RELIEF
sham device for patient-reported xerostomia severity
(P < 0.002), xerostomia frequency (P < 0.05), quality of
life impairment (P < 0.01), and swallowing difficulty
(P < 0.02). At the end of stage II, statistically significant
improvements were verified for patient-reported xerostomia severity (P < 0.0001), xerostomia frequency (P <
0.0001), oral discomfort (P < 0.001), speech difficulty
(P < 0.02), sleeping difficulty (P < 0.001), and resting
salivary flow rate (P < 0.01).
Conclusion. Our findings indicate that daily use
of the device alleviated oral dryness, discomfort, and
some complications of xerostomia, such as speech and
sleeping difficulties, and increased salivary output. The
results show a cumulative positive effect of the device
over the period of the study, from baseline to the end of
the trial.
Xerostomia, i. e., the subjective sensation of dry
mouth, is a hallmark of Sjögren’s syndrome (SS). This
symptom is frequently associated with difficulties in
swallowing, speech, and sleeping. Xerostomia may indicate that salivary output is decreased, exposing patients
to a higher risk of dental caries, periodontal diseases,
and oral infections (1,2). Salivary secretion is regulated
by an autonomic reflex arch. Afferent impulses induced
by chemical (gustatory) stimulation, mechanical stimulation (such as chewing food, tactile perception of
foreign bodies in the mouth, or mouth muscles, e. g.,
tongue movements), or electrical stimulation of the oral
mucosa are carried to the solitary nucleus in the medulla
via the facial (VII) and glossopharyngeal (IX) nerves.
Stimuli coming from other areas of the body, such as
smell and sight, are also integrated in the solitary
nucleus. Efferent signals to the sublingual and submandibular glands are transmitted through the facial nerve
via the submandibular ganglion and to the parotid
glands through the glossopharyngeal nerve via the otic
ganglion, leading to salivation (3–5).
Relief of xerostomia is achieved by increasing
oral moisture using over-the-counter oral comfort
agents or systemic sialagogues. Although safe, the
former provide only transient alleviation, requiring frequent application. Systemic sialagogues are effective in
the relief of xerostomia, but have potential systemic
adverse effects (6). It would thus be desirable to have a
therapeutic tool combining the efficacy of systemic
sialagogues with the safety of local agents. Such a
treatment could exploit the existence of the salivary
reflex by stimulating it electrically rather than pharmacologically.
Recently, an electronic intraoral device was de-
181
Figure 1. The intraoral electrostimulation device with the electronic
circuit on the lingual side (A) and with the electronic circuit on the
buccal side (B), switched on and off by the remote control.
veloped in the context of a European Union–funded
R&D project (IST-2001-37409). It was tested on patients with xerostomia, with the assumption that it would
enhance the salivary reflex. Those experiments, in which
electrostimulation was delivered to the oral mucosa for
10 minutes, resulted in a significant decrease in oral
dryness (7). The purpose of the present study was to test
the efficacy and safety of the electrostimulation device in
a long-term, prospective, multicenter trial. The primary
end point was improvement of xerostomia, and the
secondary ones were improvement of associated symptoms, increased salivary output, and the absence of
adverse events.
PATIENTS AND METHODS
Device description. The intraoral electrostimulation
device consists of a mouthpiece casted individually to fit the
mandibular dental arch and an infrared remote control
(Figure 1). It contains an electronic circuit (with a microprocessor and a receiver of remote control signals), a pair of
stimulating electrodes, and a battery. The electrodes directly
contact the oral mucosa in the mandibular third molar area, in
proximity to the lingual nerve. Thus, no conductive gel is
needed to convey electrostimulation to the tissue.
The patient activates and deactivates the electrical
stimulation by pressing the “on” and “off” buttons of the
remote control, respectively. The electrical current is of low
intensity and is not felt by the patient. An amber light that
blinks upon activation of the remote control ensures that the
device is working as intended. Failure to blink means that
the device is not functional and needs to be returned, and
that a new one has to be ordered.
Study design. The study was conducted in full accordance with the World Medical Association Declaration of
Helsinki and the additional ethics requirements of the countries where the research has been carried out. The study was
approved by all ethics boards and registered at ClinicalTrials.
gov (US National Institutes of Health; identifier
NCT00509808), indicating an estimated target of 200 patients
(in case the interim results required increasing the number of
182
subjects determined in the sample size calculation), with
investigators of each center being asked to completely evaluate
up to 10 patients. All study subjects provided written informed
consent.
Xerostomia patients were recruited from the following
14 institutions in 13 countries: Charité Universitätsmedizin
Berlin (Berlin, Germany), Hebrew University (Jerusalem, Israel), Hospital Clı́nico San Carlos (Madrid, Spain), Indiana
University (Indianapolis, IN), Istanbul University (Istanbul,
Turkey), Malmö University (Malmö, Sweden), McGill University (Montreal, Ontario, Canada), Universidad El Bosque
(Bogotá, Colombia), Universidad Nacional Autónoma de
México (UNAM; Mexico City, Mexico), Universidade de
Brasilia (Brasilia, Brazil), Università di Palermo (Palermo,
Italy), University of Helsinki (Helsinki, Finland), University of
Kentucky (Lexington, KY), and University of Zagreb (Zagreb,
Croatia). Patients with xerostomia due to SS and other conditions were eligible. SS patients were diagnosed by the referring
or participating (in the study) rheumatologists using the
American–European Consensus Group criteria (8). Standard
codes for diagnosis were not used due to the variety of
diagnoses that could be considered in the screening process.
Excluded from the study were those younger than 18 years old;
patients with human immunodeficiency virus, hepatitis C virus
infection, or other severe diseases except for chronic graftversus-host disease (GVHD); patients using anticoagulants,
pacemakers, or defibrillators; patients with an allergy to the
materials used in the electrostimulation device; patients with
mental disease or depression; pregnant women; patients with
chronic or recurrent, erosive or ulcerative, or premalignant or
malignant oral lesions; patients with oral anatomic characteristics precluding the use of the device; and patients showing
poor oral hygiene. Patients taking systemic sialagogues were
asked to discontinue their medication for at least 7 days before
commencement of the study and during the first 2 months of
the trial. Their compliance was validated using questionnaires.
This prospective randomized crossover trial was divided into 2 stages. The first stage (stage I) aimed to determine
whether electrostimulation has an additive effect on mechanical stimulation achieved by the device’s foreign body effect in
the mouth. The second stage (stage II) aimed to assess the
long-term effects of the device on xerostomia parameters.
During both stages, patients were instructed to use the device
not more than once every hour but otherwise as many times as
they liked every day.
In stage I, the electrostimulation device was used for 10
minutes at a time in either sham mode (mechanical stimulation) or active mode (mechanical and electrical stimulation),
each for 1 month, in a double-blind manner. This time period
was chosen since it was previously used in a preliminary
proof-of-principle study, in which the device was used in a
clinic for 10 minutes (7). The sequence of sham and active use
was assigned randomly to each patient and was generated and
managed centrally by the coordinating unit using the Microsoft
Excel randomization tool. Randomization was neither blocked,
due to the crossover study design, nor was it stratified, due to
uncertainty about which patient characteristics might influence
response to treatment. Identical-looking remote controls were
assigned to each patient, with precoded software commands
set for either not activating (sham) or activating (active) the
electrical stimulation upon pressing the “on” button, in accor-
STRIETZEL ET AL
dance with the randomization sequence. Each remote control
was used in a randomly assigned order (first month or second
month). The patients were blinded with regard to the type of
stimulation (mechanical only or mechanical-electrical). The
local investigators were also blinded with regard to the status
of the randomization and performed the outcome assessment
in a blinded manner. Patients received each remote control at
the beginning of the month for which it should be used. Thus,
the first remote control was collected before the second one
was delivered.
Stage II was an open-label phase, during which only
active devices were originally planned to be used for 9 months
after the completion of stage I in order to assess the cumulative
effect of electrostimulation from baseline, throughout the
active month of stage I until the end of the study. At the
beginning of the study, together with the stage I randomization, patients were also randomly allocated to use the device
during stage II either 1, 5, or 10 minutes at a time. In the
present study we analyzed the results of stage I and the first
3 months of stage II (hereinafter “stage II”) for a total of 5
months of followup, in order to enable comparison of its
findings to the findings of the few previous high-quality studies
that have evaluated other therapies for xerostomia over 3–6
months (9–11).
Outcome measures. The devices were manufactured by
the company that initiated the study, Saliwell Ltd., using
impressions obtained from the patients’ dental arches. Saliwell
Ltd. provided the devices, but did not provide honoraria to the
investigators or support to their local research infrastructure to
perform the study. After baseline, when the device was delivered to the patients and stage I started, the clinical followup
consisted of 3 outcome assessments: 1) the end of the first
month, 2) the end of the second month and the beginning of
stage II, and 3) the end of the fifth month. At each followup
visit, questionnaires were administered, whole saliva was collected, and safety-related information was obtained. The primary outcome (severity of xerostomia) and patient-centered
secondary outcomes were measured using a previously validated questionnaire (12,13). Answers to 5 questions were
reported using 100-mm visual analog scales (VAS) running
from the worst condition on the left end to the best on the right
end of the line. Questions were: “How dry is your mouth
today?” (dryness severity), “How comfortable is your mouth
today?” (oral discomfort), “How do you rate your quality of
life today?” (QOL), “How difficult is it for you to speak
because of your dry mouth?” (speech difficulty), and “How
difficult is it for you to swallow because of your dry mouth?”
(swallowing difficulty). Two additional questions were: “How
often does your mouth feel dry?” (dryness frequency, with the
possible responses always, frequently, occasionally, and never,
rated 1, 2, 3, and 4, respectively) and “During the past week,
how many times on average did you wake up in the night due
to dryness of your mouth?” (sleeping difficulty).
Other secondary outcome measures were resting and
mastication-stimulated salivary flow rates, which were always
assessed during morning hours. Patients were requested to
take nothing into their mouths for 90 minutes or longer, and
then to spit during 5 minutes into containers (catalog no.
25174; F. L. Medical), while avoiding swallowing. Salivary flow
was stimulated by chewing a piece of Parafilm. Saliva volume
ELECTROSTIMULATION DEVICE FOR XEROSTOMIA RELIEF
183
was determined gravimetrically (assuming a specific gravity of
1) (14).
As safety-related secondary outcome measures, vital
signs, changes in health condition, and oral mucosal status
were assessed. Any oral mucosal abnormality, e.g., discoloration, swelling, ulceration, or erosion, was recorded, as was any
oral discomfort caused by the electrostimulation device and
any device adjustment that consequently became necessary.
Statistical analysis. Based on previously reported reduction of xerostomia after 17 weeks of use of an antixerostomia agent (15), a sample size of 72 subjects was calculated to
be necessary to detect a difference of 11 points on a VAS with
an SD of 13 for a 2-sided test with 95% power and a 5% level
of significance (16). The total number of subjects to be recruited was 110, assuming an attrition rate of 35%, which is to
be expected in a long-term trial in which most subjects are
elderly persons who are asked to repeatedly visit the clinic
without monetary incentive.
Due to the absence of a washout period during stage I,
the carryover effect was investigated using an analysis of
variance for crossover design (17). The normality and equal
variance assumptions were checked using the normal probability plot, residuals versus predicted, the Anderson-Darling
test, and Levene’s test (18).
For stage II analyses, the mixed model was used for
analysis of variance with repeated measures to examine the
time trend in each one of the outcome parameters. Several
covariance structures were applied: compound symmetry, unstructured, and autoregressive. The most appropriate model
was chosen according to Akaike’s information criterion
(19,20). Pairwise comparisons between periods of device use
were conducted using Hochberg’s adjustment method for
multiple comparisons (21). Differences between the mucosal
status in the patient subgroups were analyzed using chi-square
and Wilcoxon tests. Parameters were compared between the
patients with and those without SS at baseline, at the end of
stage I, and at the end of stage II, using 2-sample t-tests.
Patients who were diagnosed as having conditions other than
SS were pooled together due to the small number of patients
with each condition. Statistical associations between VAS
scores and resting salivary flow rates were calculated using
Spearman’s rho. Due to the small number of subjects per
center, the analyses were not adjusted for study center. Statistical analyses were performed by one of the authors (GRBM)
and by the Statistics Unit of the Tel-Aviv Sourasky Medical
Center, using SAS for Windows, version 9.1.3 (22).
RESULTS
Figure 2. Disposition of the patients. AE ⫽ adverse event; GVHD ⫽
graft-versus-host disease.
Characteristics of the patients. As shown in
Figure 2, after screening of 171 patients for eligibility, a
total of 114 patients (intent-to-treat population) were
evaluated and randomized between December 2006 and
November 2009. Ninety-six patients (84%) completed
stage I, and 79 patients (69%) completed stage II.
Twenty-two patients were lost to followup due to lack of
satisfaction with the electrostimulation device (n ⫽ 6),
adverse events not related to device use (n ⫽ 8), familial
problems (n ⫽ 2), joining a GVHD trial (n ⫽ 1),
commuting difficulties (n ⫽ 2), or without explanation
(n ⫽3). The adverse events considered not to be related to device use were psychiatric/psychological problems (n ⫽ 2), general health deterioration (n ⫽ 1),
stiffness of the neck as complication of radiotherapy
(n ⫽ 1), pneumonia (n ⫽ 2), hospitalization due to
100
0
0
0
0
34 ⫾ 23
1.8 ⫾ 0.7
39 ⫾ 24
54 ⫾ 23
42 ⫾ 24
36 ⫾ 26
2.0 ⫾ 1.8
108 ⫾ 152
45 (0–748)
415 ⫾ 545
132 ⫾ 20
77 ⫾ 13
73 ⫾ 9
6
57
11
8
4
20
34 ⫾ 24
1.8 ⫾ 0.7
37 ⫾ 25
55 ⫾ 24
47 ⫾ 28
42 ⫾ 30
1.9 ⫾ 1.7
123 ⫾ 155
57 (0–748)
452 ⫾ 522
130 ⫾ 19
78 ⫾ 12
73 ⫾ 9
14
0
100
0
0
0
32 ⫾ 28
1.6 ⫾ 0.7
31 ⫾ 27
49 ⫾ 26
46 ⫾ 32
25 ⫾ 29
2.2 ⫾ 1.8
38
54 ⫾ 11
Radiotherapy
(n ⫽ 14)
143 ⫾ 159 35 ⫾ 63
94 (0–639) 12 (0–230)
502 ⫾ 490 256 ⫾ 426
128 ⫾ 17 125 ⫾ 20
80 ⫾ 11
77 ⫾ 12
72 ⫾ 10
72 ⫾ 9
22
8
0
28
19
9
45
34 ⫾ 26
1.8 ⫾ 0.7
35 ⫾ 27
57 ⫾ 25
54 ⫾ 32
49 ⫾ 34
1.8 ⫾ 1.6
63
57 ⫾ 13
Other
than SS
(n ⫽ 48)
0
0
0
100
0
40 ⫾ 25
1.5 ⫾ 0.6
24 ⫾ 9
77 ⫾ 10
80 ⫾ 15
69 ⫾ 34
0.6 ⫾ 1.3
0
51 ⫾ 17
GVHD
(n ⫽ 5)
147 ⫾ 175 164 ⫾ 155
66 (0–480) 108 (48–392)
463 ⫾ 401 713 ⫾ 511
129 ⫾ 10
115 ⫾ 11
80 ⫾ 9
75 ⫾ 2
77 ⫾ 8
65 ⫾ 8
25
100
0
0
100
0
0
41 ⫾ 23
1.8 ⫾ 0.7
42 ⫾ 27
60 ⫾ 23
56 ⫾ 33
54 ⫾ 33
2.2 ⫾ 1.1
89
61 ⫾ 11
Medications
(n ⫽ 9)
199 ⫾ 168
150 (0–639)
624 ⫾ 519
131 ⫾ 17
82 ⫾ 11
71 ⫾ 10
15
0
0
0
0
100
31 ⫾ 27
1.9 ⫾ 0.8
37 ⫾ 29
57 ⫾ 26
53 ⫾ 32
57 ⫾ 32
1.7 ⫾ 1.6
78
58 ⫾ 13
Other or
idiopathic
(n ⫽ 20)
146 ⫾ 176
84 (0–748)
414 ⫾ 437
131 ⫾ 18
78 ⫾ 13
73 ⫾ 10
16
53
11
11
2
24
36 ⫾ 26
1.9 ⫾ 0.7
38 ⫾ 27
55 ⫾ 23
48 ⫾ 29
42 ⫾ 30
2.0 ⫾ 1.9
80
59 ⫾ 12
Sham
(n ⫽ 56)
101 ⫾ 129
30 (0–508)
488 ⫾ 593
129 ⫾ 20
78 ⫾ 11
72 ⫾ 9
12
62
13
5
5
15
32 ⫾ 23
1.6 ⫾ 0.7
36 ⫾ 23
55 ⫾ 25
47 ⫾ 28
58 ⫾ 38
1.8 ⫾ 1.5
81
60 ⫾ 11
Active
(n ⫽ 58)
Intervention
76 ⫾ 111
30 (0–380)
353 ⫾ 462
133 ⫾ 25
79 ⫾ 13
69 ⫾ 9
7
44
19
13
0
25
32 ⫾ 25
1.8 ⫾ 0.9
34 ⫾ 28
53 ⫾ 28
46 ⫾ 29
37 ⫾ 32
1.5 ⫾1.6
83
64 ⫾ 11
Excluded
from stage I
(n ⫽ 18)
183 ⫾ 224
108 (0–748)
434 ⫾ 403
125 ⫾ 13
73 ⫾ 12
71 ⫾ 10
27
44
6
6
17
28
30 ⫾ 26
1.7 ⫾ 0.8
37 ⫾ 29
54 ⫾ 24
41 ⫾ 33
32 ⫾ 34
2.0 ⫾ 2.1
75
55 ⫾15
Excluded
from stage II
(n ⫽ 20)
Followup status†
116 ⫾ 137
57 (0–550)
467 ⫾ 557
131 ⫾ 19
80 ⫾ 12
74 ⫾ 9
12
63
10
9
1
17
34 ⫾ 24
1.7 ⫾ 0.7
37 ⫾ 24
56 ⫾ 23
49 ⫾ 27
44 ⫾ 29
2.0 ⫾ 1.6
82
60 ⫾ 10
Finished
the study
(n ⫽ 79)
* Except where indicated otherwise, values are the mean ⫾ SD. Only the parameters speech difficulty and swallowing difficulty differed significantly between patients with
Sjögren’s syndrome (SS) and patients with all other diagnoses grouped together (P ⬍ 0.05). Only the parameters dryness frequency and swallowing difficulty differed significantly
between patients in the sham intervention group and patients in the active intervention group (P ⬍ 0.05). There were no significant differences for any of the parameters between
patients who were excluded from stage I, patients who were excluded from stage II, and patients who completed the study. GVHD ⫽ graft-versus-host disease; QOL ⫽ quality
of life; RSFR ⫽ resting salivary flow rate; SSFR ⫽stimulated salivary flow rate; BP ⫽ blood pressure.
† Three patients were excluded from the analysis for stage I (due to use of systemic sialagogues) but were still allocated to intervention in stage II.
‡ Scored on a visual analog scale ranging from 0 (worst) to 100 (best).
§ Scored on a scale of 1–4, where 1 ⫽ always, 2 ⫽ frequently, 3 ⫽ occasionally, and 4 ⫽ never.
¶ Percent of patients with ⱖ1 lesion.
94
62 ⫾ 10
81
60 ⫾ 11
All patients
SS
(n ⫽ 114) (n ⫽ 66)
Diagnosis
Baseline characteristics of the patients with xerostomia*
% female
Age, years
Diagnosis, % of
patients
SS
Radiotherapy
Medications
GVHD
Other or idiopathic
Dryness severity‡
Dryness frequency§
Discomfort‡
QOL‡
Speech difficulty‡
Swallowing difficulty‡
Wake up,
times per night
RSFR, ␮l/minute
Mean ⫾ SD
Median (range)
SSFR, ␮l/minute
Systolic BP, mm Hg
Diastolic BP, mm Hg
Heart rate
Oral mucosal
changes, % of
patients¶
Table 1.
184
STRIETZEL ET AL
ELECTROSTIMULATION DEVICE FOR XEROSTOMIA RELIEF
arthritis (n ⫽ 1), and deterioration of GVHD (n ⫽ 1).
Intervention was discontinued for 11 patients because of
adverse device reaction (oral mucosal soreness [n ⫽ 2]),
poor cooperation with the investigators (n ⫽ 3), device
malfunction (n ⫽ 1), and withdrawal of centers from the
trial (McGill University following the expiration of a
funding grant [n ⫽ 1] and UNAM due to logistical
difficulties [n ⫽ 4]). Due to the use of systemic sialagogues, 3 patients were excluded from the analysis in
stage I, and 2 others were excluded from the overall
analysis due to incomplete data.
Figure 2 shows that dropout occurred at random
and was not related to the randomization assignment
when subjects were lost to followup. The data in Table 1
show that patients who dropped out at any stage were
not different from those who finished the study. The
outcomes of stage I for those who completed this part of
the study but dropped out later were similar to those for
patients who completed the whole study (Table 2).
There were not enough data on patients who dropped
out before the end of stage I for outcome measures to be
analyzed.
The baseline characteristics of the patients are
displayed in Table 1. The mean age of participants was
60 years (range 19–78 years). As expected, the majority
(81%) were women (23). Patients had xerostomia due to
SS (57%), radiotherapy to the head and neck (11%), use
of medications (8%), GVHD (4%), and other or idiopathic reasons (20%). The characteristics of the group of
patients with xerostomia due to SS and the group of
patients with xerostomia due to all other causes pooled
together were similar, except for speech difficulty and
swallowing difficulty, which were more severe in the SS
group. The subgroups of patients with diagnoses other
than SS displayed mostly similar baseline characteristics.
However, the patients with xerostomia due to radiotherapy had lower salivary flow rates, and patients with
GVHD had a higher rate of mucosal changes. Baseline
characteristics were generally similar between the
groups that were initially randomized to receive sham
and active interventions in stage I, except for dryness
frequency, which was worse in the active intervention
group and swallowing difficulty, which was more severe
in the sham intervention group. Resting salivary flow
rate was positively and weakly correlated with the VAS
scores at all 4 outcome assessments, as all ␳ values were
⬍0.45. Fourteen percent of the patients displayed oral
mucosal changes; medication intake was registered in
79%, and 53% used xerogenic drugs.
The average daily cumulative length of use of the
electrostimulation device was 40 minutes for stage I
185
(e.g., use of the device 4 times per day for 10 minutes
each time) and 21 minutes for stage II, ranging from 1
minute (e.g., 1 time per day for 1 minute each time) to
80 minutes (e.g., 8 times per day for 10 minutes each
time). Throughout the study, the tested parameters were
similar among patients with SS and all other patients
pooled together.
Efficacy. In stage I, no significant carryover and
sequence effects were found for any of the variables.
Thus, the effects of the sham and active interventions
were used for comparison regardless of their allocation
schedule. The active intervention was superior to sham
for the primary outcome measure (dryness severity;
P ⬍ 0.002) (Figure 3). The active intervention also
performed better than sham for some secondary outcome measures, either with statistical significance
(P ⬍ 0.05 for dryness frequency, P ⬍ 0.01 for QOL, and
P ⬍ 0.02 for swallowing difficulty), or with a tendency
toward statistical significance (P ⫽ 0.07 for speech
difficulty) (Table 2). No statistical significance was detected between the active and sham interventions for the
parameters oral discomfort, sleeping difficulty, resting
salivary flow rate, and stimulated salivary flow rate.
The length of use subgroups (1, 5, and 10 minutes) in stage II were pooled because no significant
differences were detected between them for the tested
variables, except for dryness frequency (for 1-minute use
versus 5-minute use) and stimulated salivary flow rate
(for 1-minute use versus 10-minute use) (P ⬍ 0.05 for
both) (Table 2). From baseline until the end of stage II
all parameters improved in the active intervention
group, except for QOL, swallowing difficulty, and stimulated salivary flow rate. The primary outcome dryness
severity (P ⬍ 0.0001) (Figure 3) and the secondary
outcomes dryness frequency (P ⬍ 0.0001), oral discomfort (P ⬍ 0.001), speech difficulty (P ⬍ 0.02), sleeping
difficulty (P ⬍ 0.001), and resting salivary flow rate (P ⬍
0.01) all improved.
Improvements in the dryness severity and resting
salivary flow rate parameters occurred in 70% and 63%
of the participants, respectively. Nine patients started
the study with a resting salivary flow rate and stimulated
salivary flow rate of 0. In 7 of these patients, saliva could
be collected at the end of stage II and dryness severity
improved. Fifteen patients took a systemic sialagogue
before joining the study. After the period of prohibition
(stage I), one-third of them resumed taking those medications.
Safety. No significant changes in vital signs were
detected. In 14% of the followup visits, patients reported
a change in their health status, i.e., modification in
–
–
–
–
–
40 ⫾ 24
1.9 ⫾ 0.7
40 ⫾ 23
50 ⫾ 24
49 ⫾ 28
44 ⫾ 27
1.9 ⫾ 1.7
–
–
–
–
–
34 ⫾ 24
1.7 ⫾ 0.7
38 ⫾ 25
56 ⫾ 23
47 ⫾ 28
43 ⫾ 30
60.5
9
7
4
19.5
–
–
–
–
–
–
–
NA
NA
NA
NA
NA
NA
NA
NA
P†
NS
126 ⫾ 17
78 ⫾ 11
74 ⫾ 11
15
130 ⫾ 18
78 ⫾ 12
73 ⫾ 9
14
–
–
–
–
NS
NS
–
–
–
–
–
–
–
–
–
–
–
–
–
63
10
9
1
17
82
60 ⫾ 10
79
Characteristics
74 ⫾ 9
12
80 ⫾ 12
131 ⫾ 19
467 ⫾ 557
116 ⫾ 137
2.0 ⫾ 1.6
37 ⫾ 24
56 ⫾ 23
49 ⫾ 27
44 ⫾ 29
34 ⫾ 24
1.7 ⫾ 0.7
–
–
–
–
–
–
–
–
Baseline
72 ⫾ 10
11
78 ⫾ 11
129 ⫾ 19
522 ⫾ 634
130 ⫾ 157
1.7 ⫾ 1.3
42 ⫾ 22
54 ⫾ 23
53 ⫾ 26
48 ⫾ 28
43 ⫾ 23
2.0 ⫾ 0.6
–
–
–
–
–
–
–
–
72 ⫾ 12
10
77 ⫾ 14
127 ⫾ 16
527 ⫾ 649
162 ⫾ 187
1.4 ⫾ 1.3
46 ⫾ 24
55 ⫾ 23
56 ⫾ 27
49 ⫾ 27
47 ⫾ 24
2.1 ⫾ 0.7
–
–
–
–
–
–
–
–
End of
All lengths
“active” stage I of usage pooled
NA
NA
NA
NA
NA
NA
NA
NA
P‡
75
6
9.5
0
9.5
91
59 ⫾ 12
32
1-minute
use§
NS
NS
NS
NS
NS
⬍0.01
⬍0.001
⬍0.001
NS
⬍0.02
NS
22
1.0 ⫾ 1.2
45 ⫾ 24
54 ⫾ 24
54 ⫾ 30
47 ⫾ 29
46 ⫾ 24
1.9 ⫾ 0.7
50
14
9
0
27
77
59 ⫾ 9
25
1.1 ⫾ 1.4
43 ⫾ 26
54 ⫾ 24
58 ⫾ 25
47 ⫾ 30
40 ⫾ 27
2.0 ⫾ 0.7
60
12
8
4
16
76
62 ⫾ 8
71 ⫾ 16
4
79 ⫾ 11
130 ⫾ 18
74 ⫾ 9
9
78 ⫾ 9
123 ⫾ 13
72 ⫾ 8
18
74 ⫾ 19
127 ⫾ 18
773 ⫾ 798 417 ⫾ 550 335 ⫾ 416
21
–
–
–
–
–
–
–
–
–
–
–
–
–
48
4.5
4.5
14
29
76
55 ⫾ 14
1.9 ⫾ 2.6
39 ⫾ 21
56 ⫾ 23
52 ⫾ 22
51 ⫾ 26
42 ⫾ 20
2.1 ⫾ 0.9
–
–
–
–
–
–
–
–
Active
71 ⫾ 10
15
76 ⫾ 10
122 ⫾ 18
69 ⫾ 19
16
76 ⫾ 7
121 ⫾ 14
428 ⫾ 378 506 ⫾ 443
138 ⫾ 145 150 ⫾ 147
2.5 ⫾ 2.7
33 ⫾ 26
47 ⫾ 25
42 ⫾ 27
45 ⫾ 27
34 ⫾ 25
1.8 ⫾ 0.6
–
–
–
–
–
–
–
–
Sham
Stage I results for patients who
dropped out during stage II
5-minute 10-minute
use§
use§
Characteristics
166 ⫾ 170 179 ⫾ 209 136 ⫾ 196
1.4 ⫾ 1.4
52 ⫾ 28
59 ⫾ 23
62 ⫾ 28
55 ⫾ 27
⬍0.0001 49 ⫾ 29
⬍0.0001 2.4 ⫾ 0.6
Results at the end of
stage II
Results for patients who completed stage II
* NA ⫽ not applicable; NS ⫽ not significant. See Table 1 for other definitions.
† Effect on baseline status of active versus sham interventions. The 95% confidence intervals (95% CIs) for the observed baseline means of the variables that were significantly different were ⫺3.7, 5.6 for the sham
intervention and 4.2, 13.7 for the active intervention for dryness severity; ⫺0.03, 0.27 for the sham intervention and 0.09, 0.38 for the active intervention for dryness frequency; ⫺9.5, ⫺0.5 for the sham intervention and
⫺5.1, 3.2 for the active intervention for QOL; and ⫺3.5, 6.8 for the sham intervention and 1.2, 10.9 for the active intervention for swallowing difficulty.
‡ Time trend from baseline. The 95% CIs for the means of the variables that were significantly different were 29, 40 for baseline, 37, 48 for the end of the active month of stage I, and 42, 53 for the end of stage II for
dryness severity; 1.6, 1.9 for baseline, 1.9, 2.2 for the end of the active month of stage I, and 2.0, 2.3 for the end of stage II for dryness frequency; 32, 43 for baseline, 37, 47 for the end of the active month of stage I,
and 41, 52 for the end of stage II for discomfort; 43, 55 for baseline, 47, 59 for the end of the active month of stage I, and 50, 62 for the end of stage II for speech difficulty; 1.6, 2.4 for baseline, 1.4, 2.0 for the end of
the active month of stage I, and 1.1, 1.7 for the end of stage II for wake up; and 85, 147 for baseline, 94, 166 for the end of the active month of stage I, and 120, 204 for the end of stage II for RSFR.
§ The only significant differences among the time of use groups were for dryness frequency (between the 1-minute use and 5-minute use groups) and SSFR (between the 1-minute use group and the 10-minute use group)
(P ⬍ 0.05 for both comparisons).
¶ Scored on a visual analog scale ranging from 0 (worst) to 100 (best).
# Scored on a scale of 1-4, where 1 ⫽ always, 2 ⫽ frequently, 3 ⫽ occasionally, and 4 ⫽ never.
** Percent of patients with ⱖ1 lesion.
71 ⫾ 12
16
77 ⫾ 11
NS
NS
470 ⫾ 532 415 ⫾ 545 520 ⫾ 602
–
126 ⫾ 18
NS
NS
1.7 ⫾ 1.6
2.0 ⫾ 1.7
132 ⫾ 161 123 ⫾ 144 134 ⫾ 155
NS
⬍0.01
0.07
⬍0.02
–
42 ⫾ 21
54 ⫾ 22
53 ⫾ 26
48 ⫾ 26
43 ⫾ 2
⬍0.002
2.0 ⫾ 0.7 ⬍0.05
–
–
–
–
–
–
–
–
Active
–
–
–
–
–
–
Sham
96
Baseline
80
58.8 ⫾ 11
Characteristics
Results for patients who completed
stage I
Description of study outcome measures*
Number of
patients
% female
Age, mean ⫾ SD
Diagnosis, % of
patients
SS
Radiotherapy
Medications
GVHD
Other or
idiopathic
Dryness severity¶
Dryness
frequency#
Discomfort
QOL¶
Speech difficulty¶
Swallowing
difficulty¶
Wake up, times
per night
RSFR,
␮l/minute
SSFR,
␮l/minute
Systolic BP,
mm Hg
Diastolic BP,
mm Hg
Heart rate
Oral mucosal
changes, %
of patients**
Table 2.
186
STRIETZEL ET AL
ELECTROSTIMULATION DEVICE FOR XEROSTOMIA RELIEF
187
Figure 3. Severity of xerostomia, the primary outcome. A, Response to treatment, measured by change in visual analog scale (VAS) from baseline to the end of stage I. The sham
intervention consisted of mechanical stimulation with the device, and the active intervention
consisted of mechanical and electrical stimuli together. There was a significant difference
between the sham and active interventions (P ⬍ 0.002). The 95% confidence intervals (95%
CIs) observed for the sham and active groups were ⫺3.7, 5.6 and 4.2, 13.7 mm, respectively.
Bars show the mean ⫾ SEM (n ⫽ 96 patients). B, VAS scores at baseline, at the end of stage
I, and at the end of stage II. Bars show the mean ⫾ SEM (n ⫽ 79). There was a significant
difference in scores over time (P for trend ⬍ 0.0001). The 95% CIs for baseline, the end of
the active month of stage I, and the end of stage II were 29, 40; 37, 48; and 42, 53 mm,
respectively.
medication (52%), diagnosis of a new disease (45%),
and surgery (3%), none of which were linked to the
study.
In 34 (14%) of 246 followup visits, an oral
mucosal finding was recorded. In 4 patients (all with
GVHD) lichenoid changes, which are characteristic of
the condition, were already present before the receipt of
the electrostimulation device, and persisted throughout
the study. All other lesions were mild, and were described as erythema, and as aphtha in one case. Oral
mucosal lesions that could be related to the use of the
device (because adjustment of the device yielded resolution of the lesions) were observed in 27% of the
patients, mostly at one followup visit.
DISCUSSION
The primary study end point (improvement in
the severity of xerostomia) and the secondary ones
(improvements in the other symptoms, increased salivary output, and event-free use) were fully met in the
present investigation. Electrostimulation delivered by
the activated device had an additive effect to mechanical stimulation by the sham device for the parameters
dryness severity (P ⬍ 0.002), dryness frequency
(P ⬍ 0.05), QOL (P ⬍ 0.01), and swallowing difficulty
(P ⬍ 0.02) and was not inferior to the sham device for
any of the other parameters. During both stages of the
study, the conditions that improved significantly during
use of the activated device were dryness severity
(P ⬍ 0.0001), dryness frequency (P ⬍ 0.0001), oral
discomfort (P ⬍ 0.001), speech difficulty (P ⬍ 0.02),
sleeping difficulty (P ⬍ 0.001), and resting salivary flow
rate (P ⬍ 0.01). No worsening of the other parameters
was observed (Table 2).
The finding that the differences between the
active and sham interventions were free of carryover and
sequence effects validated the study design, which did
not include a washout period. The blindedness of the
trial was ensured by the absence of any sensation upon
electrostimulation, the use of the same device for the
active and sham interventions, and the identical-looking
activating and nonactivating remote controls.
In the present study, the symptom profile of the
patients with SS was similar to that of all other patients,
i.e, the symptoms and consequences of oral sicca were
similar in all patients with xerostomia. Treatment of
xerostomia is mainly symptomatic and nonspecific, with
the same therapeutic agents being applied in all cases
(24). Therefore, the efficacy of a xerostomia treatment is
best evaluated by questionnaire (25). As in previous
studies (10,11), salivary flow rates were used as secondary outcome measures since no gold standard regarding
a flow rate value that distinguishes between normal and
abnormal currently exists (26). Moreover, the results of
the present study confirm the poor relationship between
the xerostomia-related symptom profile and whole salivary flow rate. However, it has been suggested that
minor gland saliva, which is poorly reflected in whole
salivary flow rate, might affect subjective feelings of dry
mouth (26). Thus, minor salivary flow rate may be
188
STRIETZEL ET AL
Table 3. Comparison between the present trial and previous studies that used systemic sialagogues in patients with xerostomia
Author, year
(ref.)
No. of
patients
Dropout
rate, %
Underlying
diagnoses
Xerostomia
severity, %
responders
Resting salivary
flow rate, %
responders
Patients with
adverse
effects, %
Agent
Duration,
months
Fox et al,
1991 (9)
Pilocarpine, 5 mg
three times daily
6
39
21
Diverse
84*
67†
84
Vivino et al,
1999 (10)
Petrone et al,
2002 (11)
Pilocarpine, 5 mg
four times daily
Cevimeline, 30 mg
three times daily
3
373
13
Not mentioned
51
197
18
Sjögren’s
syndrome
Sjögren’s
syndrome
61
3
66
Not mentioned
48
Present study
Electrostimulation
5
114
16 (in
each
stage)
Diverse
70*
63*
27
Types of adverse effects
Systemic (sweating, sensation
of warmth or flushing,
urgency of urination)
Systemic (sweating, urinary
frequency, flushing)
Systemic (headache,
sweating, abdominal pain,
nausea, sinusitis, diarrhea,
pharyngitis)
Local (oral mucosal lesions)
* Assessed at study end, compared to study baseline measurements.
† Assessed at followup visits, where posttreatment measurements were compared to pretreatment (visits’ baseline) measurements.
assessed in future studies in order to investigate whether
the function of those glands might be influenced by
activity of the electrostimulation device.
The present results were compared with those of
similarly designed high-quality studies (9–11) that were
included in two recent systematic reviews (24,27). In
Table 3, comparisons are drawn for xerostomia severity,
as a primary outcome measure, and for resting salivary
flow rate, since resting saliva is experienced by individuals for most of the day (28). The table shows that,
although of similar efficacy, the intraoral electrostimulation device appears to be safer than approved medications to treat xerostomia, as the latter frequently cause
systemic side effects. Such effects may also jeopardize
the double-blind protocol of drug studies. In contrast,
long-term use of the device resulted only in local, mild,
and transient adverse events unrelated to its active
ingredient, i.e., electrostimulation.
As in the studies to which the present one is
compared (9–11), a potential limitation of the trial is the
occurrence of missing data, which is inevitable in this
particular clinical context. Fortunately, statistical analyses suggest that this did not result in any systematic bias.
It is recognized that some of these cases may be outcome
related, such as for patients who dropped out due to lack
of satisfaction with the electrostimulation device,
dropped out without explanation, or used systemic sialagogues. The risk of missing data in this study was
anticipated due to the long duration of the trial, the
advanced age of the patients, the lack of payment
offered to them, and the nature of the condition that was
treated, i.e., xerostomia, although a debilitating disorder, has no fatal consequences. A strategy aimed at
handling missing data has been devised, including investigation of the pattern of missing data in previous trials
on similar indications for related medicinal products
(9–11), augmenting the required sample size by 35%,
and statistically modeling the data. In future research,
investigators will have to consider increasing the sample
size to allow for stratification according to the duration
of the xerostomia disorder before enrollment, since it
would be reasonable to think that structurally less affected glands in early disease would be likely to respond
better to the electrostimulation device.
The lack of improvement in self-assessed overall
QOL, as opposed to all other parameters, could be
explained by the impact on QOL of confounding factors
other than xerostomia, such as keratoconjunctivitis sicca
in SS (23), other comorbidities common in the elderly,
and cancer- and treatment-related complications among
the patients who underwent radiation (29). The smaller
decline of QOL in the active intervention group is
consistent with the direction of findings observed for
other outcomes.
Electrostimulation applied on afferent pathways
through the oral mucosa or on the skin covering the
salivary glands has previously been shown to increase
salivary production and relieve xerostomia in patients
with SS and patients who had received radiotherapy
(29–32). The electrodes of the device are placed in
proximity to the lingual nerve (33). Thus, the salivary
reflex is likely evoked through the excitation of (a)
somatic afferent A beta fibers of the trigeminal nerve
innervating oral mucous membranes and (b) visceral
afferent fibers from the tongue and efferent secretomotor fibers innervating the submandibular and sublingual
salivary glands, all relayed from, and to, the facial nerve
via the chorda tympani (34–36).
The distance between the nerves and the stimulating electrodes is an important factor in the excitation
provoked by an electrical current (36). When the device
is manufactured, the electrodes are placed close to the
ELECTROSTIMULATION DEVICE FOR XEROSTOMIA RELIEF
estimated location of the lingual nerve, but the actual
distance may vary from 1 to 4 mm (33), limiting the
predictability of the strength of the stimulating effect. In
contrast, the results of this study suggest that the duration of stimulation may play a negligible role in the
response potency.
It has been postulated that electrostimulation
augments normal physiologic salivary reflexes (30). A
study of the effect of transcutaneous nerve stimulation
on radiotherapy-induced xerostomia demonstrated an
increase in citric acid–primed salivary production lasting
longer than the length of treatment delivery (29). Thus,
it is hypothesized that long-term administration of electrostimulation could lead to resetting of the salivary
reflex, which would become more responsive to all kinds
of stimuli besides electrostimulation. In addition, stimulation of the salivary reflex arch might increase the
release of nonadrenergic, noncholinergic trophic mediators and antiapoptotic stimuli, which might have longterm trophic effects on salivary gland parenchyma, leading to the regeneration of functional tissue (37–39). This
assumption is based on studies that have demonstrated
mitogenic responses in rat parotid and submandibular
glands following electrical stimulation of their parasympathetic nerves (5).
Our results showed that the positive outcome
obtained with the electrostimulated device was due to a
cumulative effect over the period of the trial. Given the
progressive nature of xerostomia, no improvement in
patients’ symptoms and clinical signs may be anticipated
without intervention (40–42). Moreover, an eventual
placebo effect is not sustained over time, as has been
suggested in previous studies (43). Therefore, it seems
that a prolonged treatment course with electrostimulation (e.g., at least 2 months) is to be recommended.
The improvement observed among patients who
started the study with no collectable saliva is notable. It
would be expected that a stimulatory device would only
be effective for those patients demonstrating residual
salivary gland function. However, as illustrated here, the
absence of spitted saliva does not necessarily mean that
salivary glands have ceased functioning completely. In
summary, the intraoral electrostimulation device appears to be a physiologically sound, beneficial, and safe
therapeutic option for the alleviation of xerostomia.
ACKNOWLEDGMENTS
The investigators from the Universidade de Brasilia
are grateful for the collaboration of Dr. Raquel Allegretti. The
investigators from Universidad El Bosque acknowledge the
189
logistical assistance of the members of Unidad de Investigación Básica Oral-UIBO. The investigators from the University
of Helsinki are grateful to Eija Kaila, MSc, Maija Eerola, BSc
(Dentistry), and Bindu Sumathikutty, DDS, for their contributions. The authors thank the participating patients.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Wolff had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Strietzel, Lafaurie, Alajbeg, Pejda, Tran,
Martı́n-Granizo, Maniegas Lozano, Zunt, Yepes, Elad, Zeevi, Beiski,
Wolff, Konttinen.
Acquisition of data. Strietzel, Lafaurie, Alajbeg, Pejda, Vuletić, Mantilla, Falcão, Leal, Barreto Bezerra, Tran, Ménard, Kimoto, Pan,
Martı́n-Granizo, Maniegas Lozano, Zunt, Krushinski, Melilli, Campisi,
Paderni, Dolce, Yepes, Lindh, Koray, Mumcu, Elad, Zeevi, Aldape
Barrios, Beiski, Wolff, Konttinen.
Analysis and interpretation of data. Strietzel, Lafaurie, Bautista
Mendoza, Pejda, Falcão, Leal, Barreto Bezerra, Tran, Zunt, Yepes,
López Sánchez, Beiski, Wolff, Konttinen.
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efficacy, relief, multicenter, randomized, safety, tria, devices, electrostimulation, intraoral, xerostomia
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